The frequent spread of certain cancers to lymph nodes often
necessitates surgery or radiation therapy that damages the lymphatic
system and can cause lymphedema, a condition of localized fluid
retention that often increases susceptibility to infections.

The researchers of the University of Helsinki, Finland, and the Ludwig
Institute of Cancer Research show that application of vascular
endothelial growth factor-C (VEGF-C) to replace excised mouse lymph
nodes and lymph vessels ensures formation of mature lymphatic vessels
and incorporation of lymph node transplants into existing lymphatic
vasculature. An improved outcome of lymph node transplantation is
evidenced by improved lymphatic drainage and restoration of normal
lymphatic vascular anatomy in VEGF-C-treated mice.

The ability to transfer lymph nodes that reconstitute a functional
network of lymphatic vessels in adult tissues is of particular
importance in cancer follow-up therapy, as lymph nodes can prevent
systemic dissemination of metastases. Accordingly, VEGF-C-treated
lymph nodes were more effective in trapping metastatic tumor cells
than control transplants.

It has been estimated that approximately 20-30% of patients that have
undergone irradiation or surgery of the armpit in response to lymph
node metastases develop lymphedema later on. Damage to the large
collecting lymphatic vessels, which resemble smaller veins, causes the
vast majority of all lymphedemas. It has been estimated that several
million patients suffer from such acquired lymphedema worldwide. The
treatment of lymphedema is currently based on physiotherapy,
compression garments and occasionally surgery, but means to
reconstitute the collecting lymphatic vessels and cure the condition
are limited.

The Finnish researchers applied vascular endothelial growth factor-C
(VEGF-C) gene therapy in mice after surgery removal of axillary lymph
nodes, a procedure that mimicked removal of axillary lymph nodes in
patients in response to metastatic breast cancer. They found that
treatment of lymph node-excised mice with adenoviral VEGF-C gene
transfer vectors induced robust growth of the lymphatic capillaries,
which gradually underwent an intrinsic remodeling, differentiation and
maturation program into functional collecting lymphatic vessels,
including formation of uniform endothelial cell-cell junctions and
intraluminal valves.

As VEGF-C quite potently increases the rate of lymph node metastasis,
the researchers sought to develop a mode of therapy that could be
safely applied also in patients that had been treated for cancer. They
established that the VEGF-C therapy greatly improved the outcome of
lymph node transplantation. As a result, they were able to reconstruct
the normal gross anatomy of the lymphatic network in the axilla,
including both the lymphatic vessels and the nodes, suggesting that
VEGF-C therapy combined to autologous lymph node transfer is feasible
in the clinical setting.

The advantage of this rationale is increased patient safety in
instances of recurrent malignancies, as the transplanted lymph nodes
provide an immunological barrier against systemic dissemination of
cancer cells, as well as other pathogens.

The findings demonstrate for the first time that growth factor therapy
can be used to generate functional and mature collecting lymphatic
vessels. This, combined with lymph node transplantation, allows for
complete restoration of the lymphatic system in damaged tissues, and
provides a working model for future treatment of lymphedema in
patients. Effective lymph node transplantation holds tremendous
potential for immunotherapy applications in the treatment of diseases
such as cancer and chronic infections. Furthermore, the findings
encourage the use of growth factor therapy to enhance the vascular
integration and viability of transplanted tissues.

The group is currently pursuing this form of therapy in larger animal
models in order to eventually treat lymphedema patients. Further the
group aims to discover methods that would accelerate lymphatic vessel
maturation.